| First Author | Matsubara T | Year | 2012 |
| Journal | J Lipid Res | Volume | 53 |
| Issue | 12 | Pages | 2698-707 |
| PubMed ID | 23034213 | Mgi Jnum | J:190937 |
| Mgi Id | MGI:5450777 | Doi | 10.1194/jlr.M031773 |
| Citation | Matsubara T, et al. (2012) TGF-beta-SMAD3 signaling mediates hepatic bile acid and phospholipid metabolism following lithocholic acid-induced liver injury. J Lipid Res 53(12):2698-707 |
| abstractText | Transforming growth factor-beta (TGFbeta) is activated as a result of liver injury, such as cholestasis. However, its influence on endogenous metabolism is not known. This study demonstrated that TGFbeta regulates hepatic phospholipid and bile acid homeostasis through MAD homolog 3 (SMAD3) activation as revealed by lithocholic acid-induced experimental intrahepatic cholestasis. Lithocholic acid (LCA) induced expression of TGFB1 and the receptors TGFBR1 and TGFBR2 in the liver. In addition, immunohistochemistry revealed higher TGFbeta expression around the portal vein after LCA exposure and diminished SMAD3 phosphorylation in hepatocytes from Smad3-null mice. Serum metabolomics indicated increased bile acids and decreased lysophosphatidylcholine (LPC) after LCA exposure. Interestingly, in Smad3-null mice, the metabolic alteration was attenuated. LCA-induced lysophosphatidylcholine acyltransferase 4 (LPCAT4) and organic solute transporter beta (OSTbeta) expression were markedly decreased in Smad3-null mice, whereas TGFbeta induced LPCAT4 and OSTbeta expression in primary mouse hepatocytes. In addition, introduction of SMAD3 enhanced the TGFbeta-induced LPCAT4 and OSTbeta expression in the human hepatocellular carcinoma cell line HepG2. In conclusion, considering that Smad3-null mice showed attenuated serum ALP activity, a diagnostic indicator of cholangiocyte injury, these results strongly support the view that TGFbeta-SMAD3 signaling mediates an alteration in phospholipid and bile acid metabolism following hepatic inflammation with the biliary injury. |
